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Science. 2016 May 13;352(6287):844-9. doi: 10.1126/science.aac7272.

Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape.

Author information

1
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA.
2
Epigenetics Theme, Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA. Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA.
3
Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada.
4
Epigenetics Program and Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
5
Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
7
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
9
University Musculoskeletal Oncology Unit, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Department of Surgical Oncology and Division of Orthopedic Surgery, Princess Margaret Hospital, University of Toronto, Toronto, Ontario M5T 2M9, Canada.
10
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
11
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
12
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. The Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada.
13
Department of Medical Genetics and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario K1H 8L1, Canada.
14
Division of Orthopaedic Surgery, Montreal General Hospital, McGill University Health Centre, Montreal, Quebec H3G 1A4, Canada.
15
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
16
Human Oncology and Pathogenesis Program and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
17
Epigenetics Program and Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
18
Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, NY 10065, USA. plewis@discovery.wisc.edu nada.jabado@mcgill.ca alliscd@rockefeller.edu.
19
Department of Human Genetics, McGill University, Montreal, Quebec H3Z 2Z3, Canada. Department of Pediatrics, McGill University, Montreal, Quebec H3Z 2Z3, Canada. plewis@discovery.wisc.edu nada.jabado@mcgill.ca alliscd@rockefeller.edu.
20
Epigenetics Theme, Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA. Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA. plewis@discovery.wisc.edu nada.jabado@mcgill.ca alliscd@rockefeller.edu.

Abstract

Several types of pediatric cancers reportedly contain high-frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here we report that the H3 lysine 36-to-methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. After the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas in which novel K36M/I mutations in H3.1 are identified.

PMID:
27174990
PMCID:
PMC4928577
DOI:
10.1126/science.aac7272
[Indexed for MEDLINE]
Free PMC Article

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